[unreadable] Type I diabetes is characterized by the permanent loss of pancreatic insulin-producing beta cells. Our goal is to understand the mechanisms determining pancreatic beta cell mass, as a first step toward the development of regenerative therapies for diabetes. In collaboration with the BCBC Coordinating Center and members of the consortium, we will use transgenic mouse technology to examine the hypothesis that beta cells have a significant regenerative capacity, which is modulated by specific signals. The specific aims are to: [unreadable] 1. Develop a system for regulated ablation of pancreatic beta cells. Our preliminary studies indicate that mice can recover from a pulse of beta cell ablation. We will characterize in detail the physiological and histological aspects of ablation and recovery, in order to understand the mechanisims of beta cell regeneration. [unreadable] 2. Determine the cellular origins of regenerating beta cells. We will employ genetic lineage tracing to definitely determine the contributions of stem cells and pre-existing beta cells to beta cell regeneration. [unreadable] 3. Characterize the signals that regulate beta cell mass. The relative importance of blood-borne signals will be determined, with emphasis on the role of insulin and glucose metabolism. In addition, we will assess the significance of beta cell dedifferentiation in vivo and in vitro. [unreadable] Insights from these studies will be applied to primary beta cell cultures, with the aim of improving yield, preventing dedifferentiation and minimizing cell death [unreadable] [unreadable]